by Lone Frank
I gawp at him. Is he actually admitting that gene profiles can’t really be used for anything?
“No, I’m not. A gene profile can tell you that your probability for a given outcome – being overweight, for example – is greater or lesser but it cannot predict whether you will actually become fat.”
To illustrate the point about environmental factors, Stefánsson points to a finding in deCODE Genetics’s research. The company scientists have studied melanoma and found a variant in the gene for the melanocortin receptor that behaves very differently in different European populations. For Spaniards, the variant triples the risk of melanoma, while the same variant plays no role whatsoever among Icelanders – presumably, because the sun also plays a role. In Iceland, you can avoid sunlight without any problem, which is somewhat more difficult to do so in Spain. In Sweden, where there is more sun than in Iceland but less than in Spain, the variant in question provides a risk that falls somewhere between the other two populations.
“We have also discovered three gene variants that increase the risk of atrial fibrillation. Each of them is three times more frequent in China than in Europe, but the Chinese suffer atrial fibrillation far more rarely. That is more difficult to explain than about the sun and melanoma. And it shows that we have to understand the influence of environmental factors far better, before we can use gene profiles with great precision.”
Before I can object again, Stefánsson proceeds to yet another factor that complicates the picture. Apparently, it is not insignificant whether we inherit a gene variant from one or the other side of the family, that is, whether the gene in its time was provided by the egg, or by the sperm cell that won the fertilization race. Researchers at deCODEme could glimpse this mysterious effect, because they not only have genetic information from almost forty thousand Icelanders, but also data about their common relatives. Using a special type of analysis, they are able to see, according to Stefánsson, “one example after another” of variants that affect us differently according to which parent delivered it. For instance, deCODEme found that one such variant increases the risk of diabetes by thirty percent if it comes from your father, but decreases the risk by ten percent if it comes from your mother. These opposing effects were such that no one had noted the variant before, because in the classic studies the statistics cancelled each other out. In the Nature article reporting the discovery, the researchers were also able to identify a variant that increased the risk of skin cancer but only if it comes from the father’s side. The same effect holds true for a variant associated with breast cancer.
Stefánsson is now ready to move on to missing heritability. “The variants we have found so far do not explain a particularly large part of the heritability of different diseases,” he says.
I try not to roll my eyes. Yes, thanks, people do talk about the “dark matter” of the genome.
“You probably also know that many of them think it’s about us going out and finding a lot of rare variants,” he adds in a tone that makes it clear this idea is idiotic.
I mention that James Watson talks about rare variants, but I am ignored.
“I think it will turn out that a significant part of what we can’t explain today will be able to be explained by effects that are dependent on which parent the ordinary variants come from. On the whole, I think it will turn out that our models for inheritance are too primitive and must be changed.”
Here, he’s touched on something interesting. Textbooks that may have to be rewritten, the possibility of truly novel discoveries. But what about gene profiles – doesn’t this mean that quite ordinary people who were not born in Iceland cannot get a precise risk assessment? Because they don’t know whether a given variant comes from their father’s or their mother’s side?
Unfortunately, when I take a breath to ask more, a secretary pops her head in and reminds the boss that he’s scheduled to leave. He is on his way to an incredibly important event in California and the plane won’t wait. So, to say at least one positive thing, I hurry to tell him that I’m happy about my low risk of breast cancer. I describe, relieved as I am, how my grandmother died before she was sixty and my mother at just forty-six, but I can quickly tell from Stefánsson’s face that I’m celebrating too early.
“The common variants which we test are typically not involved in what we call familial cases. With that family history, you should get a specific test of your BRCA genes.”
This prods at some knowledge that I’ve repressed into a distant corner of my brain. Mutations on the genes BRCA1 and BRCA2 are found in two to five percent of all women, and they provide an extremely high risk for breast cancer. Upwards of eighty percent, according to some studies. Maybe I should just stick with the gene profile.
“And hope for the best? I can’t advise that,” says Stefánsson.
But I can’t see what good would come from the test. If I have BRCA mutations, I wouldn’t be able to do anything but ruin my life with chronic worry and spend all my time scurrying through the doors of the healthcare system with pleas for mammograms and ultrasounds.
“That’s not true,” he replies. “You can have a bilateral mastectomy done.”
Bilateral mastectomy. In Latin, it sounds so neutral and harmless. But is this man really sitting there telling me with cool objectivity that I should just have both my breasts removed? Get rid of it all, in the name of prevention?
“Yes, unless you consider that a fate worse than death.”
I DON’T KNOW if I do. But I can’t get it out of my mind for the rest of the day. Of course, I know that many women, as soon as they get a positive BRCA test, have their breasts removed and replaced by silicone. Whereas this radical solution was considered extreme just five to ten years ago, it has become almost mainstream in the United States.
Back at the hotel, I go immediately to the computer and find Myriad Genetics, the American company that has a patent on a diagnostic test of BRCA genes. They provide a quick questionnaire that is supposed to tell me whether the test can be used. They ask whether anyone in the family has had breast cancer before they were fifty, to which I answer yes. Then, I learn that I could easily have an increased risk for both breast cancer and ovarian cancer. And if I were an Ashkenazi Jew this risk would be even further increased, Myriad kindly explains. As I now know, I’m not, but the company’s BRCA analysis can clarify the issue for me, and as they emphasize: “Understanding your risk of cancer is the first step toward managing it.”
You can move on to a table and calculate your risk for having BRCA mutations, and with only one close relation who developed breast cancer before fifty, I’m down to 4.5 per cent. That is, just under a five percent risk of having gene variants that provide between a sixty-five percent and eighty percent risk of developing breast cancer. From which, of course, there is a varying risk of dying – depending on when the cancer is discovered and how it is treated.
The question is whether just under five percent is so small that I should simply pretend it’s not there – according to the homepage, there is, after all, a ninety-five percent chance that my BRCA genes are in great shape. And if they are, because I am lucky to be free of certain other variants, I have just under an eight percent risk of developing breast cancer, according to my gene profile from deCODEme. On the other hand, wouldn’t it be better to get rid of the uncertainty about whether the worst could happen once and for all?
Just one more test.
I’ll have to think about it.
I STEP BACK and examine the genomic experience inside out and upside down. What do you get from a gene profile? If you were to look at it critically, you could say that, for all its more or less transparent risk calculations, it does nothing but remind you that you really shouldn’t think you are healthy just because you think things are going well. In reality, “healthy” people are just patients who haven’t yet been diagnosed. And once this acknowledgment has been solidly planted in your mind, you just wait around to get sick, right?
Ther
e is a minor army of ethicists and social scientists with an interest in medical technology who, from time to time, air the view that it is impossible for ordinary people to benefit from having access to these new genetic tests. Ordinary people just can’t relate to the percentages with which Kári Stefánsson and his people fill their heads, and the information makes them nervous. The consequence is that they will be constantly running to their doctors, burdening an already overburdened system. They will live a more worried, stressful, poorer, and, perhaps, shorter life.
Many opinion makers and commentators are also unconvinced by the new testing opportunities. They include the British journalist Camilla Long of the Sunday Times, who penned a long, passionate tract in favor of prohibiting consumers from having direct access to genetic services. Referring to the percentages for risk of various diseases, she asks, “… who – in their right mind – would want to know? … The impact on one’s life of that kind of Damoclean diagnosis is almost impossible to imagine.” Her gloomy conclusion for society: “The cost to our collective mental health is incalculable.”
It sounds logical enough that people would feel burdened, but I don’t think it holds water. At any rate, I don’t feel that way. With my trip to Reykjavik at a proper distance, I can see that my deCODEme results have not emboldened my inner hypochondriac. I don’t sit around brooding over the possibility of having my legs amputated because of PAD or, for that matter, of developing glaucoma and going blind. The risk is there, of course – and it is even relatively high – but it would be there regardless of whether I had been handed a number for it or walked around in my pre-swab ignorance. Admittedly, the thing about BRCA is lurking and nagging deep inside me, but no more than it did before.
On the whole, my degree of nervousness and anxiety about disease and death has not changed in any notable way. There is no unambiguous answer as to whether genetic predictions will make people nervous or not. Some will take it calmly, while others will freak out at a slightly increased risk of cardiovascular disease. And they will be the same people who, with the knowledge we already have, adopt a calm, wait-and-see attitude or become wild hypochondriacs. The reaction has to do with the individual’s temperament and attitude rather than the information itself
So, the big question is whether I will change anything, do anything differently in my life, now that I have this specific, tangible genetic knowledge. Do I see myself in a new way? Have I managed to rewrite my future?
Perhaps, but not in the workout-three-hours-a-day or remove-my-breasts mode that Stefánsson suggested. Instead, in a sense, I feel more present in my biology. Or maybe I should rather say I view myself to a higher degree as an organism.
I know it sounds strange. Especially because the concept of an organism brings to mind a being low on the evolutionary scale – microbes, worms, that sort of thing. Human beings are people or individuals, not organisms. But it is as if I have been given an extra insight into myself, an X-ray vision that does not see the person but rather a well-organized, teeming whole of perpetually communicating cells.
The idea of being an organism is surprisingly agreeable, almost cheering. It’s as though the idea itself removes the burden of being an individual, because you can see yourself from a much grander perspective. My gene profile has given me an insight into some of my organism’s strengths and weaknesses, but also, at the same time, knowledge of the buttons that I can regulate.
Just a moment, the critics will say: We all know that we can and should keep the old carcass in better shape; we can all rattle off the standard health advice in our sleep. What’s new about that?
Conceded. We know it intellectually – but the feeling that you are an organism and that you are dynamic and malleable is much stronger and comes through more powerfully as a desire to shape yourself. A desire to do something. It is not just that, knowing that I have more than a thirty percent chance of developing glaucoma, I have made an appointment with my eye doctor to have the pressure in my eyeballs checked. Rather, I’m not going to drag myself to the fitness center under a heavy cloud of sluggishness. Nor do the weights and machines there continue to make me tired; now, they positively exhilarate me. While running on the treadmill, I imagine the complicated biochemical processes going on in my leg muscles, how all these splendid chemicals are being pumped into my bloodstream, and how they’ll eventually get to my brain, where they’ll influence my mood, my thoughts, and, essentially, my outlook on the world.
My personal deCODEme gene profile has opened a tiny window into this physical inner self, and it is like peering into a new dimension: a strange inner universe of digital information that unfolds and is transformed into physical manifestations we can sense and measure. A tiny piece of information comes into play in certain cells in the eye and, suddenly, the pressure in the eye is increased and your vision becomes poorer. Another genetic slipup makes beta cells in the pancreas become lazy and to produce too little insulin – with diabetes as the consequence. I dig into my raw data, wanting more. In the special genome browser that deCODEme makes available, I leaf at random through my million SNPs and get used to their strange names: the prefix rs, a number that states its position on a given chromosome, and then the two bases you have been given at that position from each parent: rs4610 (T,C). But, honestly, how can we only have found fifty diseases out of a million genetic markers? There must be more.
AFTER A FEW late evenings spent this way, I find something that can give me a fix. Promethease, it is called. The work of two idealistic Americans, Michael Cariaso and Greg Lennon, Promethease is a free computer program that can wring information out of the deCODEme data by linking individual SNPs with the scientific studies that have investigated their meaning. Cariaso and Lennon wrote their code in 2007, and put it on the Internet for general use. There it stays, developing alongside the research, because Promethease has a built-in function that constantly monitors the major scientific databases for new articles dealing with SNPs. Every time a new connection between gene variants and traits is published, the program incorporates it into the collection and users get it with their reports.
“We get at least ten thousand hits a month,” Cariaso tells me via a Skype connection from Amsterdam. “It’s not hard to squeeze out massive quantities of genetic data, but to get them interpreted and into the hands of the individual customer is a completely different question. In the future, it will be a crucial competitive parameter for companies that want to sell genetic analyses.”
That sounds very likely. At any rate, I took my hit, pulling my raw data down from deCODEme’s server and sending it to a server in the United States, where Promethease is hosted, and I’ve now got a report safe and sound on my hard disk. Instead of the fifty or so conditions deCODEme decided to tell me about, I can now see over four thousand specific SNPs listed. It’s enough to give me sweaty palms. The many variants are arranged into a handful of boxes marked with titles such as “Most Interesting SNPs,” “Medicines,” “Medical Conditions,” and “SNPs Most Unique to You.” There is also a catch-all box: “Even More Complicated.”
Cariaso has generously offered to help me examine my report. “I can quickly see if there is anything interesting, and I promise to get rid of the file immediately afterward,” he assures me.
I’m not shy about my genes, however. In fact, I have no qualms at all about having a complete stranger look at them on his computer without being there myself. It’s one of the paradoxes of the genome: on the one hand, my genes constitute all the essential information there is about me, but on the other, they are at such an abstract level that they don’t seem very private at all.
“Hey, Lone! You are the first rs8177374 (T,T) I’ve ever seen!” Cariaso writes quickly via e-mail. I almost blush. It appears that two percent of the Caucasian population is fortunate enough to have T,T in this position. To judge from the literature, that T,T is very good to have.
“A beneficial mutation that provides resistance to several diseases, such as invasive pneumoco
ccal disease, bacteremia, malaria, and tuberculosis,” Promethease supplies.
Very good.
“Beyond that, your report is quite unremarkable,” says Cariaso. “But remember that boring genes are good genes. If you have an interesting report, it means trouble.”
Excellent. I throw myself into the Promethease interface. First, I tackle the category for SNPs that have something to do with medical conditions, and I’m quickly attracted by rs2217262. It plays a role in the development of autism, it appears. Almost nine out of ten Caucasians have two As at this position in the gene DOCK4, while the rest have a C or an A or two Cs. I myself belong to the last group and, according to one study, we have less than half the general risk for autism. As it says in the article in Wikipedia to which you can click through directly from Promethease: “This is a protective gene variant.”
Now, autism is nothing to worry about as a forty-three-year-old, but if I were to have children, my protective DOCK4 variant might have a soothing effect. Lord knows, it’s an academic discussion, but there is more immediate relevance in the fact that I have a variant that seems to protect against “age-related mental decay,” namely, the base T in my SNP rs3758391. It makes sense that this would offer protection, because it has to do with an old acquaintance: this SNP is found in the middle of a gene named SIRT1, which has long been a focus for aging research. The gene appears in similar versions throughout the animal kingdom. Even yeast cells have a corresponding gene, which if it mutates give the puny creatures a longer life.
In human beings, , for example, a study of a thousand sturdy Finns over eighty-five years old shows that the bearers of at least one T were cognitively better off and even showed a slight tendency toward better heart health than did other people. I’m a little annoyed that I also have a single C – I would rather have been among the rarer, and presumably better protected, T,T genotype – and wonder where the C comes from. I only remember one case of dementia in the family. My maternal grandfather’s mother, whom everyone just called “granny,” survived in fine physical shape well into her nineties, but was lost to dementia in her last years. In the halls of the old people’s home, she waited for the bus and couldn’t understand where her little boy had gone. It was no use telling her that he had retired long ago.